Recent studies by my laboratory and collaborators and by others have demonstrated that RNA trans-splicing can correct mutations in many different genes in a wide range of disease model systems, including Huntington's disease. Trans-splicing is one of a handful of techniques that can convert the expression of a dominant negative mutation into the normal protein, thus simultaneously reducing the cause of the disease and increasing the amount of a necessary protein. Trans-splicing is the only method that can achieve these results without the requirement for cell division. We intend to develop optimal RNA trans-splicing molecules (RTMs) to repair the CAG triplet repeat expansion in exon 1 of the huntingtin gene, which is the cause of Huntington's disease. Huntingtin targeted RTMs will be evaluated for their ability to efficiently and specifically trans- splice and replace huntigtin exon 1 at the RNA level by RT-PCR, at the protein level by Western blot, and for their ability to minimize cellular toxicity in differentiated Huntington's disease patient iPSC derived striatal neurons by nuclear condensation, CellTiter-Glo Cell Viability assay, TUNEL assay, and time-lapse microscopy. 1-3 pre-clinical candidate RTMs will be identified that most efficiently correct the expression of HTT with minimal toxicity for further development.